Dipropylacetic or valproic acid (D C I) of formula ##STR1## and sodium valproate are used in human therapy for their antiepileptic properties. Thus, sodium valproate is administered in different galenic forms such as drinkable solutions or tablets. It is known that, after oral administration, the bioavailability in the blood of valproic acid is nearly 100% and that the maximum concentration, which is rapidly reached, may cause side effects.
Moreover, the production of the tablets mentioned above has a number of disadvantages which it is felt should be mentioned:
1. granulation can only be carried out in the presence of a binder and with a wetting solvent; PA0 2. before compression an adsorbent product and a lubricant must be added; PA0 3. the core thus produced can only be given a coating which dissolves in the stomach if it has already been coated with an isolating lacquer; PA0 4. the finished weight of the tablet is relatively great and the excipients represent approximately 40% of the total weight of the tablet; PA0 5. all these operations have to be carried out in a dehydrated atmosphere with a relative humidity of 30%. PA0 granulation by simply mixing valproic acid and one of the pharmaceutically acceptable salts thereof, without any solvent and hence without any drying PA0 a simplified formula PA0 a lower core weight PA0 no need to work in a dehydrated atmosphere with a relative humidity of 30% PA0 a less hygroscopic core PA0 a lower end weight for the tablet.
The present invention relates to new pharmaceutical compositions which can be administered by oral route and which contain a mixture of valproic acid and one of the pharmaceutically acceptable salts thereof.
It relates more particularly to the preparation of tablets the final weight of which is significantly less than that obtained by the conventional methods of galenic preparation.
The applicants have also discovered that the use, in the same tablet, of valproic acid combined with one of the pharmaceutically acceptable salts thereof and of a delaying excipient has the unexpected advantage of preventing the maximum blood concentration of the active principle from causing side effects (resulting from the substantial increase in the concentration of free valproic acid), whilst maintaining a blood concentration which is useful in terms of a delayed action; it also has the advantage of unexpectedly improving the process for producing the tablet and thus avoiding the various galenic disadvantages mentioned hereinbefore.
The invention thus relates to the production of pharmaceutical specialties which satisfy the above criteria.
In fact, pharmaceutical specialties are available on the market in France, containing either 200 mg or 500 mg of sodium valproate per dosage unit, the excipient used consisting of calcium silicate excipient, polyvidone excipient, magnesium stearate, talc, polyoxyethylene glycol 400, corn starch, titanium oxide, yellow iron oxide, cellulose acetophthalate and diethylphthalate, the finished weight being, for example, 800 mg in the case of the coated tablet containing 500 mg of sodium valproate, corresponding to 434 mg of valproic acid.
The processes for producing specialties based on valproic acid or one of the pharmaceutically acceptable salts thereof all use the stage of granulation carried out with a binder such as polyvidone excipient and a wetting solvent such as isopropyl alcohol or water. An absorbent product such as calcium silicate excipient and a lubricant such as magnesium stearate are added to the resulting granules before compression; after compression, the core thus produced is given an isolating coating consisting of polyvidone or methacrylate and then, if desired, an enteric release coating. Thus, the core has a weight of 562.5 mg and the isolating layer and the coating have a weight of 237.5 mg, giving a final weight of 800 mg.
It was thus thought necessary to improve the processes for preparing these pharmaceutical specialties so as to obtain a finished weight for the tablet of less than 800 mg, whilst retaining the same quantity of active principle expressed as valproic acid and the same characteristics of bioavailability.